p35 and Rac1 underlie the neuroprotection and cognitive improvement induced by CDK5 silencing.
p35 and Rac1 underlie the neuroprotection and cognitive improvement induced by CDK5 silencing.
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DOI：
10.1111/jnc.13127
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发表时间：
2015-07
影响因子：
4.7
通讯作者：
Cardona-Gomez GP
中科院分区：
文献类型：
--
作者：
Posada-Duque RA;López-Tobón A;Piedrahita D;González-Billault C;Cardona-Gomez GP
CDK5 plays an important role in neurotransmission and synaptic plasticity in the normal function of the adult brain, and dysregulation can lead to Tau hyperphosphorylation and cognitive impairment. In a previous study, we demonstrated that RNAi knock down of CDK5 reduced the formation of neurofibrillary tangles and prevented neuronal loss in triple transgenic Alzheimer’s mice. Here, we report that CDK5 RNAi protected against glutamate-mediated excitotoxicity using primary hippocampal neurons transduced with AAV2.5 viral vector eGFP-tagged SCR or CDK5 shRNA-miR during 12 days. Protection was dependent on a concomitant increase in p35 and was reversed using p35 RNAi, which affected the down-stream Rho GTPase activity. Furthermore, p35 overexpression and constitutively active Rac1 mimicked CDK5 silencing-induced neuroprotection. In addition, 3xTg-AD mice (24 months old) were injected in the hippocampus with SCR or CDK5 shRNA-miR, and spatial learning and memory were performed three weeks post injection using “Morris” water maze test. Our data showed that CDK5 knock down induced an increase in p35 protein levels and Rac activity in triple transgenic Alzheimer’s mice, which correlated with the recovery of cognitive function; these findings confirm that increased p35 and active Rac are involved in neuroprotection. In summary, our data suggest that p35 acts as a mediator of Rho GTPase activity and contributes to the neuroprotection induced by CDK5 RNAi.
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